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Mouse Model Shows Enzyme Dysfunction Associated with Depression in Huntington’s Disease

Researchers at the Neuroscience Institute of the University of Barcelona in Spain, have discovered an abnormality in a signaling enzyme in an animal model of Huntington's disease (HD), according to a study published in Biological Psychiatry on March 30. The results could explain why depressive symptoms in HD patients do not improve when treated with available antidepressants. (About 40 percent of HD patients develop depression years before motor and cognitive symptoms.) 

In the mouse model, the scientists identified significantly higher activity of an enzyme called cyclin-dependent kinase 5 (Cdk5) in the nucleus accumbens and the prefrontal cortex, two regions associated with depression and anxiety. Cdk5, a protein involved in synaptic plasticity and memory, has been linked to the cognitive symptoms in HD, but this is the first report of its association with depression in HD. The researchers saw no decreases in serotonin and dopamine, two major neurochemicals linked to depression and the target for most antidepressants.

In several standard behavioral tests, the HD mice exhibited characteristic signs of depression, but not anxiety compared with wild-type mice. To find out if lowering Cdk5 activity could reduce these depressive symptoms, the scientists identified DARPP-32/beta-adducin, a target downstream in the signaling pathway. When Cdk5 activity increases it changes how DARPP-32 acts in the brain. A balance in this pathway is critical for dopamine signaling and the stability of dendritic spines in the nucleus accumbens, said Dr. Ginés.

The investigators used drugs that target DARPP-32 to see whether it reduces depressive symptoms and inhibits cognitive and motor problems. "We are trying to modulate depression in mouse models to see if we can ameliorate motor signs and cognitive problems," said Dr. Ginés.

Ultimately, the findings could lead to the development of more targeted therapies to reduce depression in HD patients. (The serotonin-based medicines can worsen motor symptoms in some patients, as well.)

 "We think the mechanism that drives depression in these patients is different than in patients with major depression," said Sílvia Ginés, PhD, associate professor of biomedical science and senior author of the study. "We need to develop new ways to help patients with Huntington's who have depression."

The scientists are working with HD patients to collect fibroblasts to make human-induced pluripotent stem cells to see whether they can replicate any of the neurochemical abnormalities they found in the mouse model.

Link Up to More Information:

Brito V, Giralt A, Masana M, et al. Cyclin-dependent kinase 5 dysfunction contributes to depressive-like behaviors in Huntington's disease by altering the DARPP-32 phosphorylation status in the nucleus accumbens. Biol Psychiatry 2019; Epub 2019 Mar 13.